What every physician needs to know:

Infections after lung transplant are often challenging to diagnose and treat because of several complicating factors, including more severe presentations of common infections resulting from immunosuppression, uncommon infections due to immunosuppression, concomitant allograft dysfunction or rejection-mimicking infection, and significant interactions between anti-infectives and immunosuppressant medications.

The origin of infections in transplant recipients can be classified into four overlapping groups:

During the post-transplant period, the risk for particular infections varies depending on the time since the transplant procedure. These periods can be divided into three time periods.

Transplant to Day 30: Surgical complications and the risk of nosocomial infection are highest in the first 30 days. Donor-derived infections may also manifest during this period. The net state of immunosuppression depends on whether and what type of induction therapy was used. Prophylaxis for common bacterial, fungal, and viral pathogens is routinely initiated (usually trimethoprim-sulfamethoxazole and acyclovir or ganciclovir) and as a result of this and the short timeframe and limited exposure to the environment, opportunistic infections are uncommon.

Months 1-6: The risk of reactivation of latent, opportunistic infections is highest during this period, when the net state of immunosuppression is high. The risk then declines with reduction of immunosuppression to maintenance levels. The continuation of prophylactic antimicrobials can continue to reduce the risk of some bacterial pathogens and herpes viruses. Invasive fungal infections may begin to manifest during this period.

After month 6: The risk of community-acquired infections increases with exposure of the transplant patient to the outpatient setting, and the possible cessation of antiviral prophylaxis during this period may increase the risk of CMV and other herpes viruses. Depending on the recipient's overall allograft function (e.g., episodes of acute rejection or the development of bronchiolitis obliterans syndrome/BOS or chronic lung allograft dysfunction/CLAD) and overall net state of immunosuppression, they may be at greater risk for continuing opportunistic infections. The risk of malignancy, including PTLD and more common cancers, such as skin cancer, increases during this period as well.

Similarly, Candida species, filamentous fungi such as Aspergillus species, and endemic mycoses are often encountered in the post-transplant setting. Finally, with increasing global travel, parasitic infections such as Trypanosoma cruzi, the causative agent of Chagas' disease, and Strongyloides should be considered in patients who have the appropriate exposure history or who receive organs from donors with risk factors for endemic infections.

Viruses

CMV: Among solid-organ transplant (SOT) patients, lung transplant recipients have the highest risk of CMV disease, potentially a result of the large amount of lymphoid tissue in this organ which may harbour CMV and the overall higher intensity of immunosuppression. Rates of CMV infection and disease range from 30% to >80% depending on the serostatus of the donor and recipient and the use of prophylaxis. Risk factors for CMV disease include donor and recipient serostatus (highest risk is in seronegative recipient receiving an organ from seropositive donor), an increased net state of immunosuppression, the use of lymphocyte depleting agents (e.g., anti-thymocyte globulin/ATG), and host factors such as age and lymphopenia.

CMV has both direct and indirect effects on the patient. Direct effects include CMV syndrome (fever, malaise, leukopenia, or thrombocytopenia) and CMV tissue-invasive disease, which usually involves either the lungs causing pneumonitis or the GI tract which manifests as diarrhea and abdominal pain. However CMV can affect nearly every organ and cause hepatitis, CNS disease, myocarditis, and rarely retinitis. Indirect effects of CMV occur via immunomodulatory effects of the virus and may include precipitation of acute rejection or CLAD and enhance the effects of other opportunistic infections such as invasive fungal infections. Together, these effects of CMV contribute to increased mortality in SOT patients with CMV infection.

VZV and HSV: Transplant recipients are also vulnerable to other human herpes virus infections including VZV and HSV. Patients not receiving antiviral prophylaxis for CMV should receive acyclovir or other anti-herpes virus prophylaxis to prevent other herpetic outbreaks.

CARV: CARVs include influenza A and B; RSV; adenovirus; parainfluenza; coronavirus; rhinovirus; enteroviruses; human metapneumovirus; bocavirus; and polyoma viruses, such as KI and WU viruses. Yearly vaccination against influenza for transplant candidates, recipients, and close contacts should be encouraged. Infection with a CARV is more likely to progress to lower respiratory tract disease/pneumonia in lung transplant recipients and is a risk factor for CLAD.

Gram-negative bacteria:

Burkholderia species, including the B. cepacia complex, notably B. cenocepacia (genomovar III) and B. multivorans (genomovar II), are often colonizers of cystic fibrosis (CF) patients and may have implications for post-transplant antibiotic prophylaxis. Colonization with B. cenocepacia or B. gladioli in particular may predict worse post-transplant outcomes in CF patients, although B. multivorans does not appear to negatively impact survival. Because of this association, some programs view B. cenocepacia colonization as a relative contraindication for lung transplant.

Pan-resistant or MDR Pseudomonas aeruginosa is no longer considered an absolute contraindication to transplant. However, post-transplant colonization with P. aeruginosa may be predictive of CLAD. Ideally, pre-transplant data on antibiotic sensitivity patterns should be used to define perioperative strategies for infection prevention. Inhaled antibiotics such as colistin may have an important role in MDR organisms.

Non-tuberculous mycobacteria (NTM):

Multiple species of NTM including slow-growers like Mycobacterium avium complex and M. kansasii isolates, and rapid-growers like M. chelonae and M. abscessus can cause infectious complications in transplant recipients. M. abscessus in particular presents significant problems in terms of selection of effective and tolerable treatment regimens and may predict poorer outcomes if it is present as a colonizer prior to transplant. Wound infection is a common complication post-transplant, which may be difficult to manage and require surgical debridement. Recently there was a reported cluster of invasive infections from Mycobacterium chimaera in association with contaminated heater-cooler devices, which may be used in lung transplant.

Fungi:

Endemic mycoses like Histoplasma capsulatum and Coccidioides immitis typically cause disease via reactivation of latent infection in the immunocompromised host, and can present in a variety of ways. It is often difficult to distinguish reactivation from primary infection or donor-derived infection, especially when both donor and recipient reside in endemic areas. Cryptococcus is not geographically limited, and similarly may represent reactivation of latent disease, primary infection, or donor-derived infection.

Filamentous fungi such as Aspergillus can cause invasive pulmonary fungal infections, tracheobronchitis, anastomotic infections, and disseminated disease. In addition to Aspergillus, opportunistic molds including mucormoycosis, dematiaceous molds, and other hyaline molds such as Scedosporium, Fusarium, and Penicillium are capable of causing invasive infections.

Are you sure your patient has an infectious complication? What should you expect to find?

Viruses:

CMV: A diagnosis of CMV infection requires evidence of CMV viral replication via lab testing, such as PCR or antigenemia testing, while CMV disease requires evidence of CMV viral replication plus symptoms, including fever, malaise, leukopenia, or thrombocytopenia, or evidence of tissue-invasive disease, such as pneumonitis, colitis, hepatitis, or retinitis.

VZV and HSV: HSV is typically manifested by oral infection with painful ulcers around the lips and mouth, and less commonly with genital HSV. VZV may manifest as either systemic viral infection which may include diffuse rash, pneumonitis, and hepatitis, but most commonly as herpes zoster, or ‘shingles’, which may involve one or more dermatomes and may be severe in terms of extent of rash and postherpetic pain.

CARV: These viruses may present similarly to immunocompetent hosts, with fever and URI symptoms, however can rapidly progress to severe lower respiratory tract infections, which can result in significant morbidity and mortality. In lung transplant recipients, lower respiratory tract involvement may occur without an apparent URI prodrome, presenting with sudden onset of dyspnea, wheezing, and hypoxia. A more insidious onset mimicking rejection is also possible, characterized by dyspnea and PFT abnormalities without typical URI symptoms.

Gram-negative bacterial infections: These can present as in immunocompetent hosts, with involved organ systems including the lower respiratory tract, urinary tract, abdomen, bloodstream (especially in the context of indwelling catheters), and wounds.

Fungi:

Endemic mycoses: Endemic mycoses may reactivate insidiously and present with pulmonary manifestations, i.e. nodules or infiltrates, skeletal involvement including osteomyelitis and bone marrow infiltration, skin/soft tissue disease, and CNS involvement. Cryptococcosis often manifests as pulmonary or CNS disease, but it may also disseminate with fungemia. Transplant recipients with pulmonary cryptococcal disease should be evaluated for CNS involvement by LP.

Aspergillus infections: These infections can manifest in a variety of ways, including pre-transplant airway colonization and aspergilloma formation, and post-transplant tracheobronchitis, bronchial anastomotic dehiscence, invasive pulmonary aspergillosis, sinus infection, and disseminated disease. Evidence of a large pulmonary burden is concerning for CNS disease.

Candida infections: These infections, which typically occur in the first 30 days after transplant can include bloodstream infections, empyema, mediastinitis, wound infection, bronchial anastomotic dehiscence, and infection of vessel anastomoses with mycotic aneurysm formation.

Beware: there are other diseases that can mimic an infectious complication.

Patients with allograft rejection may have symptoms that mimic infection, including fever, fatigue, cough, shortness of breath, and imaging abnormalities. In addition, it is possible for both infection and rejection to present simultaneously. Drug reactions including amiodarone toxicity or pleural effusion secondary to sirolimus use may also mimic infectious complications.

How and/or why did the patient develop an infectious complication?

Lung transplant recipients are uniquely predisposed to infectious complications of the allograft for several reasons, including:

The constant exposure of the transplanted lung to the external environment

Decreased mucociliary clearance/impaired cough reflex due to denervation of allograft

Transmission of pathogens from the donor via the allograft

Infection from a diseased native lung in single-lung transplant

Ischemia or other complications of the anastomotic site

Neutropenia or lymphopenia secondary to medication side effects

The relatively high level of immunosuppression required in lung transplant

Augmentation of immunosuppression for rejection including plasmapheresis, rituximab, ATG, or steroid pulse may further increase vulnerability to infection. In addition to opportunistic infections, transplant recipients are at risk for any common pathogens that infect normal hosts; however, recipients may experience a more severe or prolonged course of disease, regardless of the site of infection. In addition, common infections may present with atypical manifestations.

Which individuals are at greatest risk of developing an infectious complication?

Viruses:

CMV: Risk factors include serostatus of the donor and recipient, with a seronegative recipient of a seropositive organ at highest risk; allograft rejection; the use of induction immunosuppression; and concurrent infections (primarily with other viruses). Areas under investigation include defects in CMV-specific cell-mediated immunity, polymorphisms in the innate immune system, and other host factors, such as lymphopenia. The CMV serostatus of the donor is determined pre-transplant or as soon as possible in the post-transplant period (recipient should be tested during transplant evaluation) so an appropriate antiviral prophylaxis regimen can be initiated. Of note, patients with inappropriately low valganciclovir dosing who are donor positive and recipient negative are at increased risk for development of ganciclovir-resistance. Lymphopenia and augmentation in immunosuppression also increase the risk for other human herpesviruses including HSV and VZV.

CARV: Unvaccinated patients are at highest risk of contracting influenza virus (A and B), so yearly vaccination is strongly encouraged for transplant recipients and their household contacts. CARVs can be transmitted as a donor-derived infection. Primary infection can occur after contact with community members and may be seen after recent travel.

Gram-negative bacteria:

CF patients are at high risk for post-transplant complications with pan-resistant or MDR Gram-negative bacteria because of the likelihood of pre-transplant colonization due to bronchiectasis, impaired mucociliary clearance, and prior antimicrobial exposure that may select for highly resistant organisms over time. Infected sinuses may harbor MDR strains.

Non-tuberculous mycobacteria:

Structural lung abnormalities, including CF, COPD, and bronchiectasis, place patients at risk for pre-transplant colonization and subsequent invasive disease after transplant. Impairment in cell-mediated immunity due to immunosuppressive medications and chronic rejection also place patients at risk.

Fungi:

Aspergillus: Risk factors include pre-transplant colonization, acquisition of colonizers during first 12 months post-transplant, and a high net state of immunosuppression. Other risks include early airway ischemia, bronchial stenting, single-lung transplant, hypogammaglobulinemia, CMV infection, use of alemtuzumab or thymoglobulin induction therapies, and acute rejection requiring augmentation of immunosuppression. Risk factors are similar for Aspergillus-like hyaline molds and mucormycosis.

Candida: Most candidal infections occur within first 30 days of transplant. Risk factors include use and duration of broad-spectrum antibiotics, presence of a central venous catheter, use of renal replacement therapy, TPN, and heavy growth of Candida from donor lung(s).

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Viruses:

CMV: Quantitative nucleic acid testing of blood specimens via PCR has become the most widely accepted method of CMV viral load monitoring. CMV antigenemia detection has fallen out of favor because of its relative insensitivity. CMV PCR standardization has significantly improved uniformity of diagnostic testing overall. Nucleic acid testing for CMV in other body fluids, such as bronchoalveolar lavage fluid (BAL) or CSF is also feasible in most centers. Positive qualitative PCR testing of BAL samples may be difficult to interpret, especially in the setting of other potential etiologies of lung infection.

A negative blood CMV PCR test does not rule out tissue-invasive CMV disease so if clinical suspicion for CMV disease remains high, additional testing should be performed. This is especially true for CMV GI involvement. CMV disease is often accompanied by hematologic changes, especially leukopenia and thrombocytopenia. Other lab abnormalities, such as liver transaminase elevations in CMV hepatitis, may be observed depending on the organ affected.

The diagnosis of tissue-invasive CMV disease should also be supported by cytology and/or biopsy specimens from the affected organ with histopathology for characteristic CMV cytopathic changes (e.g., viral inclusions) as well as viral culture results.

A promising area in CMV diagnostics is the measurement of CMV-specific cell-mediated immunity (CMI) as a predictor of the development of CMV viremia and disease after the completion of primary post-transplant prophylaxis. This QuantiFERON-CMV test was promising in one study for predicting late-onset CMV disease.

VZV and HSV: A diagnosis of localized VZV or HSV infection depends on samples of skin lesions and positive testing results either by PCR or immunohistochemistry. Given the characteristic appearance of the oral ulcers that accompany HSV, it may be possible to start empiric treatment while awaiting diagnostic testing. PCR testing of blood for HSV or VZV can assist in the diagnosis of disseminated disease.

CARV: Culture or antibody testing has now been largely replaced by PCR, either single virus-directed or panel testing which targets multiple viruses simultaneously. PCR-based quantitative nucleic acid testing for respiratory viruses from BAL or nasopharyngeal aspirates, washes or swabs is the most sensitive modality for detection of viruses such as influenza A and B, RSV, and parainfluenza.

Gram-negative bacteria: If infection is suspected, sputum and BAL specimens should be submitted for culture and susceptibility testing so antimicrobial therapy can be optimized. For pulmonary infections, deeper specimens, i.e. BAL, may be superior to sputum or tracheal aspirate culture for diagnosis. Identification of the exact strain prior to transplant is critical when B. cepacia infection is suspected/documented in CF patients so appropriate risk stratification can be performed. For infections outside the lung, appropriate cultures should be sent.

NTM: The 2007 IDSA/ATS guidelines provide guidance for approach to diagnosis and treatment, but were not designed specifically for lung transplant recipients. They recommend the following microbiologic data to support the diagnosis of NTM disease:

Positive culture results from at least one bronchial wash or lavage, OR

Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) AND positive culture for NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) AND one or more sputum or bronchial washings that are culture positive for NTM.

Identification to the species level and susceptibility data are critical, as appropriate antimicrobial regimens vary significantly by species.

In the absence of above criteria, a high index of suspicion should be maintained, and for at risk patients, especially one who is symptomatic or has radiographic evidence of infection, treatment may be considered without serial culture positivity.

Fungi:

Endemic mycoses: Diagnostic approaches to these infections include fungal culture as well as antigen testing. This includes Histoplasma urine antigen testing, cryptococcal serum antigen, and the Coccidioides antigen test. When antigen testing is unavailable, antibody testing may be used, but is limited due to the inability to delineate current from past infection, as well as a potential for false negative results in immunocompromised patients, with the exception of Coccidioides infection in which serologic testing remains the most common method for diagnosis.

Aspergillus, other molds, and Candida: Culture remains the gold standard for the diagnosis of fungal diseases, including aspergillosis and candidal infections, to identify the organism to the species level and for performance of susceptibility testing. Histopathology can suggest a diagnosis of fungal infection, but identification of the species is often difficult and unreliable.

The use of the serum galactomannan assay (EIA) for the detection of invasive aspergillus infection has not been widely adopted in SOT, mainly because of the poor sensitivity. However, if positive, this serum test may be used to measure response to treatment over time. Testing BAL samples improves the sensitivity to 60-80% for detecting invasive aspergillosis, with a specificity of 95%. False positives may be seen with beta-lactams (e.g., ticarcillin-clavulanate, IV amoxicillin, and piperacillin-tazobactam, although this cross-reactivity is rarer with current formulations), and the assay may cross-react with other molds or endemic mycoses.

The (1→3)-β-D-Glucan assay tests for a cell wall component present in most fungi, so it is not specific for aspergillus or candida species. The test also has a high false positive rate in critically ill patients and does not appear to have better sensitivity than the galactomannan test.

What imaging studies will be helpful in making or excluding the diagnosis of an infectious complication?

Chest imaging is extremely helpful in the workup of suspected pulmonary infection in transplant recipients, and it may serve as a useful guide in targeting additional diagnostic efforts, such as BAL or biopsy, and to assess the response to therapy. For CARV and pulmonary bacterial infections, chest imaging is useful in determining the extent of involvement.

CMV: A diagnosis of CMV pneumonitis may be supported by a CXR that demonstrates interstitial patterns with parenchymal consolidation and multiple small nodules. CT scans may show patchy or diffuse ground-glass attenuation. Focal consolidations, reticular opacities, thickened intralobular septa, and tree-in-bud abnormalities are also seen. Pleural effusions are present in up to 20% of patients.

Given the nonspecific nature of these findings, a combination of symptoms, imaging, laboratory, and pathological testing should be used to make the diagnosis. This strategy is especially important, as periodic shedding of CMV in seropositive individuals can occur in the absence of clinically significant disease or in the context of concurrent illness (infectious or non-infectious).

NTM: The IDSA/ATS guidelines recommend the following radiographic data to support the diagnosis of NTM disease: nodular or cavitary opacities on CXR or a CT that shows multifocal bronchiectasis with multiple small nodules. In those with baseline abnormal CTs, the appearance of new lesions may be difficult to discern and classic patterns of NTM may not be present.

Fungal: A diagnosis of invasive pulmonary aspergillosis may be supported by CT imaging, but findings are typically non-specific and require pathologic and microbiologic confirmation. The finding of a "halo" sign is often characteristic in stem cell transplant recipients, but it is not a sensitive indicator of disease in SOT. Numerous radiographic patterns, including nodules, cavitary lesions, focal infiltrates, and consolidation with subsegmental to multilobar involvement, may be seen in patients with invasive aspergillosis. Chest imaging remains normal in the majority of patients with tracheobronchial disease.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of an infectious complication?

Changes in PFTs are not specific to infectious complications but may be caused by a variety of pulmonary processes. Therefore, while these tests are not specific for diagnosis of pulmonary infections if used in isolation, they may be complementary to other diagnostic procedures.

What diagnostic procedures will be helpful in making or excluding the diagnosis of an infectious complication?

For suspected pulmonary disease due to any pathogen, bronchoscopy is typically the procedure of choice to visually assess the airways and anastomoses and to obtain specimens for culture and susceptibility testing, cytologic and pathologic examination, nucleic acid testing, or other analyses as appropriate.

Radiologically guided (e.g., CT-guided) sampling techniques are also helpful in obtaining specimens from peripheral parenchymal or pleural lesions that are not amenable to sampling via bronchoscopy. Surgical approaches like video-assisted thorascopic surgery (VATS) should also be considered when appropriate.

For non-pulmonary lesions like skin nodules, abdominal abscesses, or osteomyelitis, sampling for microbiologic (and pathologic) analysis should always be considered given the broad spectrum of potential causal pathogens and the risk of resistant organisms inherent in the lung transplant population. Careful thought should be given prior to the procedure as to what testing should be performed so sufficient material is obtained and proper procedures are followed.

CMV: In suspected CMV pneumonitis, bronchoscopy with BAL for nucleic acid testing and transbronchial biopsy specimens for pathology, if appropriate, should be collected. In the absence of PCR-based testing, viral culture or shell vial cultures may be considered. Other diagnostic procedures for extra-pulmonary CMV disease may be warranted based on symptoms and may include colonoscopy for GI disease or a dilated retinal exam for suspected retinitis.

HSV/VZV: For HSV, swab of lesions or ulcers for PCR or culture is effective for diagnosis. When VZV is suspected, vesicular lesions can be punctured sterilely and the fluid or ulcer bases sampled for PCR or viral culture. In the absence of vesicles, skin biopsy may be performed.

Fungal: For suspected invasive pulmonary fungal infections, bronchoscopy with biopsy or CT-guided biopsy with specimens for both pathologic and microbiologic analysis are preferred due to the potential of BAL contamination from upper airway colonization via environmental exposure which may not be representative of parenchymal disease.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of an infectious complication?

NTM: The diagnosis of NTM can be supported by pathology findings like granulomatous inflammation or a positive AFB stain on the tissue specimen. However, cultures should always be submitted in parallel for species identification to rule out TB (especially in pulmonary disease for public health reasons) and to guide definitive antimicrobial combination therapy.

Fungi: While pathology can assist in the diagnosis of invasive fungal disease (by filamentous fungi or endemic mycoses), identification of fungal organisms to the species level is often not definitive. Cultures should always be submitted in parallel for species identification to guide definitive anti-fungal therapy.

If you decide the patient has an infectious complication, how should the patient be managed?

CMV:

CMV Prophylaxis: Goal of CMV prophylaxis is to reduce or eliminate risk of CMV disease and associated morbidity/mortality in the early post-transplant period, as well as to decrease inflammation in the allograft which may lead to CLAD. The length of antiviral prophylaxis in lung transplant is dictated by the serostatus of the donor and recipient (with donor-positive/ recipient-negative patients at highest risk) and by the current practices of the transplant center. For lung transplant recipients, a prophylaxis-based strategy is favored given the high risk for CMV disease. Prophylaxis is defined as administration of antiviral medication to all patients starting immediately after transplant, in contrast to pre-emptive therapy, which involves intensive lab monitoring--usually weekly--for evidence of CMV viral replication with initiation of antiviral treatment once viral replication is detected to prevent progression to disease.

Guidelines from the American Society of Transplantation and The Transplantation Society provide guidance on prophylaxis strategies: Lung transplant recipients are considered high-risk regardless of CMV serostatus and universal prophylaxis is preferred.

The guidelines also point out that pre-emptive treatment has not been well studied in lung transplant, so this strategy is not recommended. Although pre-emptive therapy may reduce drug exposure, side effects, and drug costs, because of the concern for adverse impact on the lung allograft, this approach is generally not recommended.

The guidelines recommend oral valganciclovir 900 mg once a day (adjusted for renal function if appropriate) or IV ganciclovir 5 mg/kg once a day (adjusted for renal function if appropriate) for prophylaxis. Oral ganciclovir has poor bioavailability and should be avoided. The use of CMV immune globulin (i.e., Cytogam, CMV-IG) has not been well studied.

The duration of prophylaxis should be at least 6 months. Recent data suggests extending prophylaxis to 12 months or longer after transplant. Providers should consider each patient individually in terms of their post-transplant course (rejection, other illnesses, expected tapering of immunosuppression, etc.) and the tolerability of the prophylaxis regimen. Re-initiation of CMV prophylaxis should be considered in certain high-risk patients during treatment of acute rejection with prolonged high-dose steroids, the use of anti-lymphocyte antibody therapy, or other enhancement of immunosuppression. After completion of prophylaxis, monitoring by CMV PCR assessment should be continued to monitor for CMV viremia, and treatment or prophylaxis restarted if viremia is detected.

CMV Treatment: Lung transplant recipients who have isolated low-level CMV viremia, (e.g. <500 IU/ml) no signs or symptoms of CMV syndrome or tissue-invasive disease, and no other complicating factors (e.g., no concurrent rejection or illness) may be managed initially via reduction of maintenance immunosuppression and careful weekly monitoring of viral response. However, should signs/symptoms of CMV disease develop, should CMV viral load levels continue to increase despite reduction of immunosuppression, or should a transplant recipient initially present with confirmed CMV disease (evidence of CMV viral replication with attributable symptoms or evidence of tissue-invasive disease), treatment should be initiated.

Reduction of maintenance immunosuppression can be performed in conjunction with initiation of antiviral medication. Traditionally, the preferred treatment for CMV disease has been with IV ganciclovir 5 mg/kg every 12 hours (adjusted for renal function if appropriate).

For patients with isolated CMV viremia at levels <20,000 copies per milliliter, isolated CMV syndrome, or mild-moderate CMV disease without significant GI involvement, recent data suggests that oral valganciclovir 900 mg every 12 hours (adjusted for renal function if appropriate) is not inferior to IV ganciclovir in a mixed population of SOT recipients (mostly kidney transplants). Caution should be exercised in patients in whom adequate absorption of oral medications is in question and in patients who may not be compliant with oral therapy. This approach has not been studied specifically in lung transplant recipients.

Treatment should be continued for a minimum of 2 weeks AND until cessation of viral replication has been verified AND until any symptoms attributable to CMV have resolved. Quantitative nucleic acid testing or antigenemia testing should be performed weekly during treatment to follow virologic response to therapy. Confirmation of resolution of viremia with 1-2 negative tests is recommended prior to stopping therapy.

Secondary prophylaxis with valganciclovir 900 mg once a day (adjusted for renal function if appropriate) can be considered for patients at high risk of relapse after completion of CMV treatment (e.g., patients in whom reduction of immunosuppression was not possible because of concurrent rejection).

The addition of CMV immune globulin to antiviral treatment has not been well studied, but it may be useful in severe CMV disease or CMV pneumonitis. IVIG, which also contains anti-CMV antibodies, is a lower cost alternative which may provide similar benefit to CMV-IG.

Patients who fail to respond to standard antiviral therapy should be evaluated for ganciclovir-resistant CMV. In this scenario, therapy with potentially more toxic antiviral agents foscarnet or cidofovir may be necessary and should be considered in consultation with infectious diseases. Attention to fluid and electrolyte status is helpful in preventing nephrotoxicity with foscarnet.

The side effects of valganciclovir and ganciclovir usually manifest as cytopenias, especially leukopenia and thrombocytopenia. As CMV itself often causes these abnormalities, some patients need support with colony-stimulating factors like filgrastim (i.e., Neupogen) until CMV replication is fully suppressed. Renal function must be carefully monitored as both ganciclovir and valganciclovir must be dose-adjusted once creatinine clearance is <60 mL/min.

HSV/VZV: Although ganciclovir and valganciclovir have activity against these viruses, preferred treatments are acyclovir and its analogues valacyclovir and famciclovir. Patients who are donor negative/recipient negative for CMV should receive acyclovir prophylaxis 400 mg TID. Treatment of HSV encephalitis is with IV acyclovir 5 mg/kg IV q8; oral HSV can be treated with oral acyclovir or its analogues. Severe disseminated VZV or herpes zoster should be treated with IV acyclovir but less severe cases may be treatable with oral antiviral therapy.

CARV: Effective antiviral therapies for most CARV are not available, with notable exception of influenza and perhaps RSV, so appropriate infection-control strategies, including hand hygiene and droplet precautions, are mandatory to prevent spread of disease. These precautions are especially important in the healthcare setting, as transplant patients may have prolonged viral shedding after infection. Supportive care and reduction of immunosuppression, when possible, remain the mainstays of CARV treatment, and vaccination should be encouraged.

Suspected cases of influenza A or B should ideally be treated within 48 hours of symptom onset, but transplant recipients in particular may still benefit if therapy is initiated outside of this window. Symptomatic patients should be treated regardless of the duration of symptoms. Every effort should be made to establish the diagnosis of influenza, including the type, as specific antiviral therapy depends on the resistance pattern of the current circulating viruses.

In most cases, a neuraminidase inhibitor like oseltamivir or zanamivir taken twice daily is recommended for influenza A or B. Treatment should be continued for 5-10 days although there may be a benefit in extending therapy beyond this period for patients slow to clinically respond or who have evidence of continued viral shedding.

Unvaccinated patients with suspected exposure to influenza should receive prophylaxis with oseltamivir or zanamivir taken once daily for 5-10 days after the last known exposure contact. It is unknown whether vaccinated patients will benefit from prophylaxis. Seasonal or extended prophylaxis is not recommended because of concerns about emerging viral resistance.

For RSV lower respiratory tract disease, supportive care with reduction of immunosuppression, if possible, is universally recommended. The addition of high-dose corticosteroids in this setting remains controversial, and the use of ribavirin in SOT recipients continues to be debated because of the lack of randomized controlled studies. Limited data suggest benefit of aerosolized ribavirin in lower respiratory tract disease in the stem cell transplant population; however there are significant limitations to its use relating to high cost and feasibility of administration. Cohort studies support using oral ribavirin in lung transplant patients with lower respiratory tract disease with evidence of FEV1 improvement and resolution of RSV associated with ribavirin use.

Two case series suggest a role for IV or oral ribavirin in lung transplant. Both treated patients with ribavirin plus high-dose oral or IV corticosteroids until repeated nasopharyngeal swabs were negative for RSV. After median follow-up of >300 days in both studies, all subjects had full recovery of FEV1 after RSV resolution, and only one case of late BOS was seen out of 23 subjects. The oral ribavirin study reported no adverse events, and the IV study reported mild but reversible hemolytic anemia. Randomized studies are needed to fully assess the role of ribavirin.

At this time, there are no consensus recommendations for the use of palivizumab, RSV immune globulin, or steroids for treatment or prophylaxis in transplant recipients. Many experts recommend use of IVIG for symptomatic cases of RSV and other CARVs.

Gram-negative bacteria: Treatment options for MDR or panresistant Gram-negative bacterial infections must be guided by susceptibility results. Consultation with an infectious diseases specialist should be considered. Treatment often requires the use of more toxic antimicrobials, such as colistin or aminoglycosides, in combination with broad-spectrum agents.

NTM: Susceptibility testing should be performed for all clinically relevant isolates because of the evolving resistance patterns of many NTM species and isolates (e.g., M. abscessus) and because of potential drug-interaction issues with immunosuppressant agents (e.g., the use of rifampin for M. avium disease or clarithromycin for rapid-growing NTM). Susceptibility testing to evaluate for the presence of inducible macrolide resistance should be performed in cases of infection with M. abscessus and M. fortuitum. Repeat susceptibility testing should be performed if disease recurrence after treatment has occurred.

Treatment of NTM infections requires combination therapy with multiple classes of antimicrobials, potentially including IV aminoglycosides, for prolonged periods and may require surgical intervention. Therefore, consultation with an infectious diseases specialist is strongly recommended. Inhaled aminoglycosides may also have a role for maintenance therapy.

Fungi:

Fungal prophylaxis: There are no large-scale multicenter studies to guide antifungal prophylaxis, so practices vary widely from center to center. Guidelines suggest stratifying patients based on individual risk factors, including pre-transplant colonization with Aspergillus, acquisition of colonizing organisms within the first 12 months of transplant, early airway ischemia, placement of a bronchial stent, single-lung transplant, hypogammaglobulinemia, CMV infection, use of alemtuzumab or thymoglobulin induction therapies, and acute rejection that requires augmentation of immunosuppression. Other authors have supported universal prophylaxis for all lung transplant recipients to decrease invasive fungal infection as well as possible adverse effects on the lung allograft of mold colonization.

Inhaled amphotericin and oral itraconazole and voriconazole prophylaxis strategies of varying durations have been used with limited data. Itraconazole is limited by difficulties with achieving therapeutic drug levels and voriconazole has been associated with unanticipated adverse events, including disabling neuromuscular disorders and periostitis, as well as skin cancer in lung transplant patients exposed to prolonged courses. Posaconazole may be an option as it is well absorbed orally with fewer side effects. Drug interactions between azole antifungals and calcineurin (e.g., tacrolimus) and m-TOR inhibitors (e.g., sirolimus) must be considered. Additionally, therapeutic drug monitoring is recommended to ensure that drug levels are adequate and to monitor for potential toxicity.

Aspergillus tracheobronchitis treatment: Recent guidelines suggest voriconazole as first-line therapy for biopsy-confirmed Aspergillus tracheobronchitis or anastomotic infections, along with a reduction of maintenance immunosuppression. Voriconazole dosing is weight-based and must be adjusted in patients with liver impairment. In addition, the IV formulation may not be used in patients with renal insufficiency (CrCl < 50 mL/min or any type of dialysis). The typical oral dose is two loading doses of 400 mg 12 hours apart, then 200 mg orally every 12 hours.

Voriconazole has significant drug interactions because of interactions with cytochrome P450 enzymes, notably tacrolimus, which requires a significant dose reduction to avoid toxicity (to ~1/3-1/2 of original dose), and sirolimus which is relatively contraindicated with voriconazole.

Liver function tests should be monitored. Visual disturbances are a common side effect. As above, neuromuscular disorders and periostitis, as well as skin cancer, are emerging as long-term sequela of prolonged voriconazole exposure.

Second line azoles for Aspergillus and other hyaline molds are posaconazole and isavuconazole.

With the exception of A. terreus infection because of its intrinsic resistance to amphotericin B, IV lipid formulations of amphotericin B deoxycholate remain an alternative in patients who cannot tolerate azoles. There is limited experience using echinocandins (e.g., caspofungin, micafungin) for tracheobronchial infections. Approaches that are under investigation for aspergillus tracheobronchitis include inhaled and topical amphotericin. Duration of treatment is guided by bronchoscopic surveillance of trachea and anastomoses until resolution.

Invasive Aspergillosis treatment: Similar treatment guidelines apply for invasive Aspergillosis, with voriconazole recommended as first-line agent. IV lipid formulations of amphotericin B, echinocandins, and triazole agents posaconazole and isavuconazole are alternatives. Again, reduction of maintenance immunosuppression is an important component of treatment. There is no evidence to support the use of combination therapy although there may be a role for this approach in certain patient subgroups, such as those with renal insufficiency.

Recent guidelines have endorsed therapeutic drug monitoring of azole levels, as serum concentrations are highly variable among patient populations, especially in CF patients. Trough levels for voriconazole between 1-5 μg/μL are recommended for optimal efficacy and prevention of toxicity. Surgical intervention (including debridement and resection) may be necessary for life-threatening hemoptysis, lesions in close proximity to great vessels or pericardium, sino-nasal infections and intracranial lesions, and in cases of progressive or refractory disease when optimal antifungal therapy has failed. Duration of treatment is guided by clinical and radiographic resolution of abnormalities, but a minimum of 12 weeks of therapy is recommended.

Candidal tracheobronchitis: Treatment should be based on the results of cultures taken at time of bronchoscopic inspection. Culture data is critical to rule out aspergillus and to identify the candida isolate to the species level, as several species have intrinsic or dose-dependent resistance to certain antifungals, such as C. krusei and C. glabrata, which have high rates of resistance to fluconazole (C. krusei has intrinsic fluconazole resistance) and C. lusitaniae which is frequently resistant to amphotericin B. The choice of antifungal should be determined by culture results and the duration of therapy should be guided by bronchoscopic resolution of infection. Guidelines summarizing the treatment of invasive candidal infections are available from the AST and IDSA.

What is the prognosis for patients managed in the recommended ways?

Viruses:

CMV: Late onset CMV disease (defined as CMV disease that occurs after cessation of prophylaxis) is a well described entity in studies evaluating the use of universal prophylaxis. The incidence of late CMV among SOT patients is estimated to be ~30%. Risk factors include donor-positive/recipient-negative mismatch, shorter duration of prophylaxis, higher levels of immunosuppression, and allograft rejection.

Extension of CMV prophylaxis in some studies have resulted in reduced rates of CMV disease 12 months or longer after transplant. Recent data also suggest that the universal prophylaxis may not impair the ability of the immune system to generate CMV-specific T cell responses.

Recurrent CMV disease may occur in patients who have certain risk factors, including primary CMV infection (e.g., in a recipient seronegative for CMV IgG at disease onset), high baseline CMV viral load, GI or multiorgan disease, and concurrent rejection.

Multiple rounds of antiviral treatment may place a patient at risk for development of resistant CMV infection, especially if renal insufficiency complicates proper dosing of antiviral therapy.

CMV may also be a risk factor for the development of CLAD which has significant prognostic implications post-lung transplant.

CARV: CARV infection has been noted as a significant risk factor for the development of CLAD and the development of acute rejection.

Gram-negative bacterial infections: Persistent colonization with Gram-negative bacteria, especially Pseudomonas aeruginosa, after transplant has also been associated with CLAD.

NTM: Transplant patients with disseminated NTM infections are at risk for recurrent disease, often because of an inability to tolerate the difficult and lengthy antibiotic regimens required. Treatment intolerance may be due to side effects (especially from aminoglycosides), technical issues with long-term IV therapy (e.g., maintenance of central catheter), and patient fatigue that often develops after several months of combination therapy.

What other considerations exist for patients with infectious complications?

Current studies are examining the relationship between genetic polymorphisms involved in the immune response and risk for infection post-transplant but data is not yet sufficient to recommend any type of genetic screening tests for susceptibility to infection.